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Recent studies show that liver X receptor (LXR) agonists exert significant antitumor effects in a variety of tumor cell lines including hepatocellular carcinoma (HCC). But the molecular mechanisms underlying LXR antitumor activity are not fully understood. In this study we investigated the effect of LXR agonist T0901317 (T317) on HCC development and its relationship with RalA binding protein 1 (RALBP1)-associated EPS domain containing 2 (REPS2)/epidermal growth factor receptor (EGFR) signaling axis. We showed that T317 (0.1-0.5 μM) dose-dependently increased REPS2 expression in normal hepatocytes (BNLCL.2 and LO2) and HCC cells (HepG2 and Huh-7). Using promoter activity assay and chromatin immunoprecipitation (CHIP) assay we demonstrated that T317 enhanced REPS2 expression at the transcriptional level via promoting the binding of LXR protein to the LXR-response element (LXRE) in the REPS2 promoter region. We showed that the inhibitory effect of T317 on the proliferation and migration of HCC cells was closely related to REPS2. Moreover, we revealed that T317 (400 nM) increased expression of REPS2 in HepG2 cells, thus inhibiting epidermal growth factor (EGF)-mediated endocytosis of EGFR as well as the downstream activation of AKT/NF-κB, p38MAPK, and ERK1/2 signaling pathways. Clinical data analysis revealed that REPS2 expression levels were inversely correlated with the development of HCC and reduced REPS2 expression associated with poor prognosis, suggesting that REPS2 might be involved in the development of HCC. In conclusion, this study provides new insights into the potential mechanisms of LXR agonist-inhibited HCC.

Magnetic hyperthermia therapy (MHT) is a highly promising therapeutic modality, mainly applied to deal with cancers and malignant tumors. To gain efficient magnetic hyperthermia therapy, magnetic nanoparticles (Fe3O4) with improved heating efficiency are necessary. In this work, magnetite nanoparticles anchored on graphene oxide (GO/Fe3O4) have been synthesized via chemical precipitation method, and anti-cancer drug have been introduced to form GO/Fe3O4 loaded with doxorubicin hydrochloride (GO/Fe3O4-DXR) composite nanoparticles. X-ray diffraction analysis has been carried out to characterized the crystal structure of GO/Fe3O4 nanoparticles with different mass ratios. Fourier transform infrared spectroscopy (FTIR) confirmed the presence of doxorubicin hydrochloride (DRX) in GO/Fe3O4-DXR, while the structure of GO/Fe3O4 nanoparticles with different mass ratios are studied by Transmission electron microscopy (TEM). And the heating efficacy of GO/Fe3O4-DXR nanoparticles were. investigated suitable for magnetic hyperthermia therapy under safe alternating magnetic fields (80 kHz, 30 kA m−1). Besides, the DXR loading and release data of GO/Fe3O4-DXR have been tested via ultraviolet–visible spectroscopy (UVVIS) in presence of the AC field. The above characteristics conform to temperature requirements of magnetic materials on medical applications, which infers that GO/Fe3O4 -DXR particles show promising talent as targeted drug carriers and thermoseeds in MHT.

The methyltransferase-like 3 (Mettl3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for RNA N6-methyladenosine (m6A) modification, which plays an important role in gene post-transcription modulation. Although RNA m6A is enriched in mammalian neurons, its regulatory function in nociceptive information processing remains elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced inflammatory pain significantly decreased global m6A level and m6A writer Mettl3 in the spinal cord. Mimicking this decease by knocking down or conditionally deleting spinal Mettl3 elevated the levels of m6A in ten-eleven translocation methylcytosine dioxygenases 1 (Tet1) mRNA and TET1 protein in the spinal cord, leading to production of pain hypersensitivity. By contrast, overexpressing Mettl3 reversed a loss of m6A in Tet1 mRNA and blocked the CFA-induced increase of TET1 in the spinal cord, resulting in the attenuation of pain behavior. Furthermore, the decreased level of spinal YT521-B homology domain family protein 2 (YTHDF2), an RNA m6A reader, stabilized upregulation of spinal TET1 because of the reduction of Tet1 mRNA decay by the binding to m6A in Tet1 mRNA in the spinal cord after CFA. This study reveals a novel mechanism for downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons.

Xinyue Zhang,1– 3,* Jinan Guo,4,5,* Parham Jabbarzadeh Kaboli,2,6 Qijie Zhao,2 Shixin Xiang,2 Jing Shen,2,6 Yueshui Zhao,2,6 Fukuan Du,2,6 Xu Wu,2,6 Mingxing Li,2,6 Huijiao Ji,2,6 Xiao Yang,2 Zhangang Xiao,2,6 Qinglian Wen1,3 1Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 2Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Academician (Expert) Workstation of Sichuan Province, Luzhou, Sichuan, People’s Republic of China; 4The Department of Urology, The Second Clinical Medical College of Jinan University (Shenzhen People’s Hospital), The First Affiliated Hospital of South University of Science and Technology of China, Shenzhen Urology Minimally Invasive Engineering Center, Shenzhen, Guangdong, People’s Republic of China; 5Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen, Guangdong, People’s Republic of China; 6South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhangang XiaoLaboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, People’s Republic of ChinaEmail zhangangxiao@swmu.edu.cnQinglian WenDepartment of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, People’s Republic of ChinaEmail wql73115@163.comObjective: The Warburg effect, also known as aerobic glycolysis, plays a dominant role in the development of gastrointestinal (GI) cancers. In this study, we analyzed the expression of key genes involved in the Warburg effect in GI cancers and investigated the effect of suppressing the Warburg effect in vitro in liver cancer cell lines.Methods: The Cancer Genome Atlas (TCGA) RNA-Seq data were used to determine gene expression levels, which were analyzed with GraphPad Prism 7.00. Genetic alterations were queried with cBioPortal. The influence of the Warburg effect on liver cancer cell viability, migration and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity was determined by means of MTT, transwell and GAPDH activity assays.Results: The levels of expression of genes associated with the Warburg effect were increased in tumors. To our knowledge, this is the first report of upregulated expression of CUEDC2, HMGB2, PFKFB4, PFKP and SIX1 in liver cancer. Clinically, overexpression of these genes was associated with significantly worse overall survival of liver cancer patients. In vitro, selective inhibition of GADPH suppressed the growth and metastasis of Huh-7, Bel7404 and Hep3B hepatocellular carcinoma cell lines.Conclusion: The Warburg effect may play an important role in GI cancers, especially in liver cancer.Keywords: Warburg effect, gastrointestinal cancers, liver cancer, bioinformatics, GAPDH

Background: Serum uric acid (SUA) has been revealed to be positively associated with the body composition parameters in hemodialysis patients, but few studies have investigated that in patients on peritoneal dialysis (PD). The aim of this study was to identify the relationship between SUA and appendicular skeletal muscle mass (ASM) and the effect of their interaction on mortality in PD patients. Methods: This was a single-center retrospective cohort study. Patients who underwent multifrequency bioelectrical impedance analysis between January 1, 2013, and December 31, 2016, and had data on SUA values were enrolled. All patients were followed up until December 31, 2019. Results: In total, 802 prevalent PD patients (57.9% male), with mean age of 46.2 ± 14.2 years were enrolled. The average SUA and ASM were 6.8 ± 1.3 mg/dL and 21.2 ± 4.9 kg. According to multiple linear regression models, SUA was positively associated with relative ASM in middle-aged and older PD patients (standardized coefficients [β] 0.117; 95% confidence interval [CI] 0.027, 0.200; p = 0.010). Further sex-stratified analysis showed that the association existed only in males (β 0.161; 95% CI 0.017, 0.227; p = 0.023). Moreover, the presence of hyperuricemia was found to predict lower risk of all-cause mortality (hazard ratio [HR] 0.514, 95% CI 0.272, 0.970; p = 0.040) only in patients with lower relative ASM. And, the adjusted HR of every 1 mg/dL elevated SUA level was 0.770 (95% CI 0.609, 0.972; p = 0.028) for all-cause mortality in the lower relative ASM subgroup. Conclusions: There exists a positive association between the SUA and ASM, and the ASM significantly affected the association between SUA and all-cause PD mortality.

Sensitization of central pain and inflammatory pathways play essential roles in migraine, a primary neurobiological headache disorder. Since hypoxia-inducible factor-1α (HIF-1α) is implicated in neuroprotection and inflammation inhibition, herein we investigated the role of HIF-1α in migraine. A chronic migraine model was established in mice by repeated injection of nitroglycerin (10 mg/kg, i.p.) every other day for 5 total injections. In the prevention and acute experiments, roxadustat, a HIF-1α stabilizer, was orally administered starting before or after nitroglycerin injection, respectively. Pressure application measurement, and tail flick and light-aversive behaviour tests were performed to determine the pressure pain threshold, thermal nociceptive sensitivity and migraine-related light sensitivity. At the end of experiments, mouse serum samples and brain tissues were collected for analyses. We showed that roxadustat administration significantly attenuated nitroglycerin-induced basal hypersensitivity and acute hyperalgesia by improving central sensitization. Roxadustat administration also decreased inflammatory cytokine levels in serum and trigeminal nucleus caudalis (TNC) through NF-κB pathway. Consistent with the in vivo results showing that roxadustat inhibited microglia activation, roxadustat (2, 10, and 20 μM) dose-dependently reduced ROS generation and inflammation in LPS-stimulated BV-2 cells, a mouse microglia cell line, by inhibiting HIF-1α/NF-κB pathway. Taken together, this study demonstrates that roxadustat administration ameliorates migraine-like behaviours and inhibits central pain sensitization in nitroglycerin-injected mice, which is mainly mediated by HIF-1α/NF-κB/inflammation pathway, suggesting the potential of HIF-1α activators as therapeutics for migraine.

Xiao-Xiao Yang,1,2 Chao Yang,2 Li Wang,2 Ying-Bo Zhou,2 Xiang Yuan,2 Nan Xiang,2 Yi-Ping Wang,3 Xiao-Mei Li1,2 1School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, People’s Republic of China; 2The First Affiliated Hospital of USTC, Department of Rheumatology and Immunology, University of Science and Technology of China, Hefei, People’s Republic of China; 3Westmead Institute for Medical Research, University of Sydney, Sdyney, NSW, 2145, AustraliaCorrespondence: Xiao-Mei Li Email lixiaomei@ustc.edu.cnObjective: Although extensive research has been carried out on CD4+T cells infiltrating the labial glands in patients with primary Sjögren’s Syndrome (pSS), it is still unclear how CD4+T cells remain in the labial gland tissue and develop into tissue resident cells. The aim of this study was to investigate the molecular mechanism by which CD4+T reside in labial glandular tissue of pSS patients.Methods: Lymphocyte infiltration in labial salivary glands (LSG) of pSS patients was detected by H&E staining. Expression of sphingosine-1-phosphate receptor 1 (S1PR1) in LSG was examined by Immunohistochemistry. Immunofluorescence analyses were utilized to detect the co-expression of CD4, CD69 and S1PR1 in T cells of LSG of pSS patients. Expression of gene S1pr1 in peripheral blood CD4+T cells of healthy controls and pSS patients was detected by quantitative real-time PCR (QPCR). QPCR was used to examine the expression of gene S1pr1, Klf2, and Cd69 in the CD4+T cells that were co-cultured in vitro with cytokines TNF-α, TGF-β, and IL-33.Results: S1PR1 was expressed in the infiltrating monocytes in LSG of pSS patients, and S1PR1 was weakly or even not expressed in cytoplasm of CD4+CD69+TRM cells of LSG in patients with pSS. Expression of gene S1pr1 in peripheral blood CD4+T cells of pSS patients was about three-fifths of that of healthy controls (P < 0.05). Expression of genes S1pr1 (P < 0.001) and Klf-2 (P < 0.001) was significantly decreased, and the expression of gene Cd69 (P < 0.05) was significantly increased in peripheral blood CD4+T cells of pSS patients co-cultured in vitro with cytokines TNF-α, TGF-β, and IL-33.Conclusion: Our study suggests that the decrease of S1pr1 gene expression may provide a molecular basis for promoting the tissue retention and development of CD4+CD69+TRM cells.Keywords: primary Sjogren’s syndrome, S1PR1, CD4+TRM

Objective Although extensive research has been carried out on CD4+T cells infiltrating the labial glands in patients with primary Sjögren’s Syndrome (pSS), it is still unclear how CD4+T cells remain in the labial gland tissue and develop into tissue resident cells. The aim of this study was to investigate the molecular mechanism by which CD4+T reside in labial glandular tissue of pSS patients. Methods Lymphocyte infiltration in labial salivary glands (LSG) of pSS patients was detected by H&E staining. Expression of sphingosine-1-phosphate receptor 1 (S1PR1) in LSG was examined by Immunohistochemistry. Immunofluorescence analyses were utilized to detect the co-expression of CD4, CD69 and S1PR1 in T cells of LSG of pSS patients. Expression of gene S1pr1 in peripheral blood CD4+T cells of healthy controls and pSS patients was detected by quantitative real-time PCR (QPCR). QPCR was used to examine the expression of gene S1pr1, Klf2, and Cd69 in the CD4+T cells that were co-cultured in vitro with cytokines TNF-α, TGF-β, and IL-33. Results S1PR1 was expressed in the infiltrating monocytes in LSG of pSS patients, and S1PR1 was weakly or even not expressed in cytoplasm of CD4+CD69+TRM cells of LSG in patients with pSS. Expression of gene S1pr1 in peripheral blood CD4+T cells of pSS patients was about three-fifths of that of healthy controls (P < 0.05). Expression of genes S1pr1 (P < 0.001) and Klf-2 (P < 0.001) was significantly decreased, and the expression of gene Cd69 (P < 0.05) was significantly increased in peripheral blood CD4+T cells of pSS patients co-cultured in vitro with cytokines TNF-α, TGF-β, and IL-33. Conclusion Our study suggests that the decrease of S1pr1 gene expression may provide a molecular basis for promoting the tissue retention and development of CD4+CD69+TRM cells.

Dysfunctions of gene transcription and translation in the nociceptive pathways play the critical role in development and maintenance of chronic pain. Circular RNAs (circRNAs) are emerging as new players in regulation of gene expression, but whether and how circRNAs are involved in chronic pain remain elusive. We showed here that complete Freund's adjuvant-induced chronic inflammation pain significantly increased circRNA-Filip1l (filamin A interacting protein 1-like) expression in spinal neurons of mice. Blockage of this increase attenuated complete Freund's adjuvant-induced nociceptive behaviors, and overexpression of spinal circRNA-Filip1l in naive mice mimicked the nociceptive behaviors as evidenced by decreased thermal and mechanical nociceptive threshold. Furthermore, we found that mature circRNA-Filip1l expression was negatively regulated by miRNA-1224 via binding and splicing of precursor of circRNA-Filip1l (pre-circRNA-Filip1l) in the Argonaute-2 (Ago2)-dependent manner. Increase of spinal circRNA-Filip1l expression resulted from the decrease of miRNA-1224 expression under chronic inflammation pain state. miRNA-1224 knockdown orAgo2overexpression induced nociceptive behaviors in naive mice, which was prevented by the knockdown of spinal circRNA-Filip1l. Finally, we demonstrated that a ubiquitin protein ligase E3 componentn-recognin 5 (Ubr5), validated as a target of circRNA-Filip1l, plays a pivotal role in regulation of nociception by spinal circRNA-Filip1l. These data suggest that miRNA-1224-mediated and Ago2-dependent modulation of spinal circRNA-Filip1l expression regulates nociception via targetingUbr5, revealing a novel epigenetic mechanism of interaction between miRNA and circRNA in chronic inflammation pain.SIGNIFICANCE STATEMENTcircRNAs are emerging as new players in regulation of gene expression. Here, we found that the increase of circRNA-Filip1l mediated by miRNA-1224 in an Ago2-dependent way in the spinal cord is involved in regulation of nociception via targetingUbr5. Our study reveals a novel epigenetic mechanism of interaction between miRNA and circRNA in chronic inflammation pain.

The use of the phenicol antibiotic florfenicol in livestock can select for the optrA gene, which also confers resistance to the critically important oxazolidinone antibiotic linezolid. However, the occurrence and dissemination of florfenicol and linezolid cross-resistance genes in anaerobic treatment systems for livestock waste are unknown. Herein, the phenotypes and genotypes (optrA, fexA, fexB, and cfr) of florfenicol and linezolid cross-resistance were investigated in 339 enterococci strains isolated from lab- and full-scale mesophilic anaerobic digestion systems treating swine waste. It was found that optrA, fexA, and fexB were frequently detected in isolated enterococci in both systems by PCR screening, whereas cfr was not detected. The most abundant gene was optrA, which was detected in 73.5% (n = 50) and 38.9% (n = 23) of enterococci isolates in the full-scale influent and effluent, respectively. Most strains carried more than two resistance genes, and the average percentage of co-occurrence of optrA/fexA was 16.6%. Based on minimum inhibitory concentrations of the enterococci strain phenotypes, 85.7%, 77.5%, and 77.5% of strains in influent were resistant to chloramphenicol, florfenicol, and linezolid, respectively, while 56.3%, 65.2%, and 13% in the effluent isolates were found, respectively, which was consistent with the genotype results. The phenotypes and genotypes of florfenicol and linezolid resistance were relative stable in the enterococci isolated from the influent and effluent in lab-scale anaerobic digestion system. The findings signify the enterococci isolates harboring the optrA gene remained in effluents of both full- and lab-scale swine waste anaerobic digestion system; hence, effective management strategies should be implemented to prevent the discharge of antibiotic resistance from the livestock waste treatment systems.

To screening of bacteria with cyclic amino alcohol deamination activity for enantioselective synthesis of chiral cyclic β-amino alcohols. A new strain named Arthrobacter sp. TYUT010-15 with the (R)-selective deamination activity of cyclic β-amino alcohol has been isolated from nature via a high throughput solid-phase screening method. The reaction conditions of TYUT010-15 were optimized. Using the resting cell of TYUT010-15 as the catalyst, kinetic resolution of trans-2-aminocyclopentanol, trans-2-aminocyclohexanol and cis-1-amino-2-indanol was carried out to afford (1S, 2S)-trans-2-aminocyclopentanol, (1S, 2S)-trans-2-aminocyclohexanol and (1R, 2S)-cis-1-amino-2-indanol in > 99% ee and 49.6–50% conversion. Four aromatic β-amino alcohols and two amines were also resolved, (S)-β-amino alcohols and (R)-amines were obtained in > 99% ee. Preparation experiment was conducted with 200 mM (23.2 g L−1) racemic trans-2-aminocyclohexanol, yielding the desired (1S, 2S)-trans-2-aminocyclohexanol in 40% isolated yield, > 99% ee and 5.8 g L−1 d−1 space time yields. This study provides a high throughput solid-phase method for screening of bacteria with cyclic amino alcohol deamination activity and a first example for practical preparation of chiral cyclic β-amino alcohol by Arthrobacter sp. TYUT010-15.

Rationally surface optimization is considered to improve both energy capacity and structure stability in rechargeable batteries. A novel structure of copper coated silicon nanoparticles encapsulated in carbon cages (Si@Cu@CC) is synthesized by feasible methods of reduction and pyrolysis. The obtained composite exhibits a superior reversible capacity of 1724.3 mAh g−1 after 50 cycles at 0.1 A g−1, and the coulombic efficiency (CE) is 98.13%. It also maintains 1201.6 mAh g−1 even at the current density of 2 A g−1. The copper shell as a mechanical support layer wraps around the silicon nanoparticle can relieve the inner stress caused by the volumetric change. The exterior of Si@Cu particles is continuous network of carbon cages, which not only improves the conductivity of electrodes but also provides abundant transport channels for electrons and ions. The particular structure and the synergistic effect of copper and carbon have very important influence on the gorgeous properties of this composites.

Background— There is a paucity of data from large cohort studies examining the prognostic significance of obstructive sleep apnea (OSA) in patients with coronary artery disease. We hypothesized that OSA predicts subsequent major adverse cardiac and cerebrovascular events (MACCEs) in patients undergoing percutaneous coronary intervention. Methods and Results— The Sleep and Stent Study was a prospective, multicenter registry of patients successfully treated with percutaneous coronary intervention in 5 countries. Between December 2011 and April 2014, 1748 eligible patients were prospectively enrolled. The 1311 patients who completed a sleep study within 7 days of percutaneous coronary intervention formed the cohort for this analysis. Drug-eluting stents were used in 80.1% and bioresorbable vascular scaffolds in 6.3% of the patients, and OSA, defined as an apnea-hypopnea index of ≥15 events per hour, was found in 45.3%. MACCEs, a composite of cardiovascular mortality, nonfatal myocardial infarction, nonfatal stroke, and unplanned revascularization, occurred in 141 patients during the median follow-up of 1.9 years (interquartile range, 0.8 years). The crude incidence of an MACCEs was higher in the OSA than the non-OSA group (3-year estimate, 18.9% versus 14.0%; p =0.001). Multivariate Cox regression analysis indicated that OSA was a predictor of MACCEs, with an adjusted hazard ratio of 1.57 (95% confidence interval, 1.10–2.24; P =0.013), independently of age, sex, ethnicity, body mass index, diabetes mellitus, and hypertension. Conclusions— OSA is independently associated with subsequent MACCEs in patients undergoing percutaneous coronary intervention. Evaluation of therapeutic approaches to mitigate OSA-associated risk is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01306526.

Objective: To systematically evaluate the intervention effect of virtual reality technology on patients recovering from traumatic brain injury. Methods: The computer retrieved CNKI, VIP, Wan Fang, Embase, The Cochrane Library and PubMed database, and collected randomized controlled trials of virtual reality technology combined with routine rehabilitation training and simple routine rehabilitation training on patients recovering from traumatic brain injury. The retrieval period was from the establishment of the database to July 2019. Two researchers independently screened the literature, extracted the data and evaluated the risk of bias in the included studies. RevMan 5.3 software was used for analysis. Results: A total of 7 articles were included. Meta-analysis results showed that virtual reality technology could significantly improve balance function (mean difference (MD) = 3.72, 95% confidence interval (CI) (2.61, 4.83), P < 0.001), daily living ability (MD = 11.87, 95% CI (10.42, 13.32), P < 0.001), and exercise ability (MD = 3.83, 95% CI (2.30, 5.36), P < 0.001). In the aspect of posture control ability, the trajectory motion length, trajectory velocity and peripheral area were improved (standardised mean difference (SMD) = −0.80, 95% CI (−1.19, −0.41), P < 0.0001), (SMD = −0.95, 95% CI (−1.45, −0.45), P = 0.0002), (SMD = −0.69, 95% CI (−1.11, −0.26), P = 0.001). Conclusion: Virtual reality technology can significantly improve the balance function, daily living ability, motor function and postural control ability of patients recovering from cerebral trauma. Limited by the quantity and quality of the included studies, the above conclusions need to be verified by more high-quality studies.